A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I

The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1

Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement

Background: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. Design: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. Results: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients. Conclusions: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.Peer reviewedPublisher PD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Physical Activity Levels during Therapeutic Camp Activities in Youth with Disabilities in the United States

Youth with developmental disabilities (DD) face challenges that may impact their participation in physical activity. One of the biggest challenges is the availability of opportunities to engage in activities that are adapted for youth with DD. In addition, due to challenges with current physical activity assessment methods for youth with DD, the activity levels during modified activities remain unclear. The purpose of this investigation was to determine the activity levels of youth with DD during structured and unstructured activities offered during a therapeutic camp. This camp was a five-day, overnight experience in an outdoor camp center in the southeastern region of the U.S. Youth (n = 29; 14.6 ± 3.9 years) with more than one DD and with varying abilities wore accelerometers while they engaged in 13 activities of varying categories (functional/gross motor, game, sociodramatic, fine motor, free play) and contexts (ropes, horses, outdoor adventure, music and movement, yoga, come on down, sports and games, theatre, cabin challenge, arts, cooking, mad science, free play). Activity level varied by activity category and context and the intensity level of the majority of the camp activities was classified as either sedentary or light. There was a time course effect on activity; most activities resulted in a gradual decline over the session, except for cooking, sports and games, and free play. This therapeutic camp provided an opportunity for youth to engage in physical activity that would be classified as light intensity. The activities available at this camp were designed to address specific goals and objectives and provided enrichment opportunities (e.g., life skills, social skills) for youth to obtain multiple skills while using movement as a framework to deliver the content

Effect of BMI on Pedometers in Early Adolescents under Free-Living Conditions

The article reports on research which was conducted to determine whether the New Lifestyles NL-2000 (NL) and the Digi- Walker SW-200 (DW) pedometers yield similar step counts as compared with an ankle-mounted criterion, Step Watch 3, when worn by early adolescents in a free-living environment and to study whether body mass index (BMI) percentile affects the accuracy of waist-mounted pedometers in adolescents. They found that The NL and DW recorded fewer steps than the Step Watch 3 in each BMI category and that the NL is a better device for adolescents\u27 steps than the DW, especially for those who are obese

Trends in Physical Activity and Sedentary Behaviors of United States Youth

Background: Increases in childhood and adolescent obesity are a growing concern in the United States (U.S.), and in most countries throughout the world. Declines in physical activity are often postulated to have contributed to the rise in obesity rates during the past 40 years. Methods: We searched for studies of trends in physical activity and sedentary behaviors of U.S. youth, using nontraditional data sources. Literature searches were conducted for active commuting, physical education, high-school sports, and outdoor play. In addition, trends in sedentary behaviors were examined. Results: Data from the Youth Risk Behavior Surveillance System (YRBSS) and other national surveys, as well as longitudinal studies in the transportation, education, electronic media, and recreation sectors showed evidence of changes in several indicators. Active commuting, high school physical education, and outdoor play (in 3- to 12-year-olds) declined over time, while sports participation in high school girls increased from 1971 to 2012. In addition, electronic entertainment and computer use increased during the first decade of the 21st century. Conclusions: Technological and societal changes have impacted the types of physical activities performed by U.S. youth. These data are helpful in understanding the factors associated with the rise in obesity, and in proposing potential solutions

Effect of BMI on Pedometers in Early Adolescents under Free-Living Conditions

The article reports on research which was conducted to determine whether the New Lifestyles NL-2000 (NL) and the Digi- Walker SW-200 (DW) pedometers yield similar step counts as compared with an ankle-mounted criterion, Step Watch 3, when worn by early adolescents in a free-living environment and to study whether body mass index (BMI) percentile affects the accuracy of waist-mounted pedometers in adolescents. They found that The NL and DW recorded fewer steps than the Step Watch 3 in each BMI category and that the NL is a better device for adolescents\u27 steps than the DW, especially for those who are obese

Associations among Motor Competence, Physical Activity, Perceived Motor Competence, and Aerobic Fitness in 10–15-Year-Old Youth

(1) Background: The developmental model describes possible mechanisms that could impact the trajectory of children and adolescents’ health behaviors related to obesity; however, few data are available that support this model in the adolescent population. This study investigated the associations among motor competence (MC), moderate-to-vigorous physical activity (MVPA), perceived motor competence (PMC), and aerobic fitness in children and adolescents and the mediating and moderating effects of PMC, aerobic fitness, and weight status on the MC–MVPA relationship. (2) Methods: Participants included 47 adolescents (12.2 ± 1.6 y; 55% male) who completed the Bruininks–Oseretsky Test of Motor Proficiency, 2nd Edition (MC), Harter’s perceived self-competency questionnaire (PMC), and the PACER test (aerobic fitness) and whose MVPA was measured via accelerometry. The body mass index (BMI) was calculated from measured height and weight. (3) Results: There were positive correlations between MC and fitness [rs(47) = 0.469, p rs(47) = 0.682, p rs(47) = 0.416, p p > 0.05). There were inverse associations between BMI and both MVPA [rs(44) = −0.410, p rs(47) = 0.295, p < 0.05]. The association between MC and MVPA was mediated by fitness (β = 0.3984; 95% CI (0.0564–0.7985)). (4) Conclusions: The associations among MC, PMC, and fitness highlight the critical role of MC in health and partially support the proposed developmental model concerning the relationships that exist among MC, MVPA, PMC, fitness, and BMI

Effects of Toe-In and Wider Step Width in Stair Ascent with Different Knee Alignments

Purpose Toe-in (TI) and toe-in with wider step width (TIW) gait modifications have successfully reduced the internal peak knee adduction moment (KAM) during level walking and stair ascent tasks, respectively, for healthy and knee osteoarthritis populations. However, the concurrent effects of these modifications have not previously been combined to reduce both the first and the second peak KAM during stair ascent or tested among the different knee alignment groups. Therefore, the purpose of this study was to examine effects of TI and TIW gait modifications on knee biomechanics during stair ascent in individuals with varus, neutral, and valgus knee alignments. Methods Thirty-eight healthy individuals (age 18-30 yr) with varus, neutral, and valgus knee alignments confirmed using radiographs, performed stair ascent in normal, TI, and TIW gait conditions. A 3 × 3 (group × condition) mixed model repeated-measures ANOVA compared alignment groups across the stair ascent gait conditions (P \u3c 0.05). Results The TI and the TIW reduced the first peak KAM and KAM impulses compared with normal stair ascent. The TIW also reduced the second peak KAM compared with normal gait and reduced KAM impulses compared with TI. The varus group had increased first peak KAM compared with neutral and valgus groups. The TI and the TIW also reduced peak knee flexion moments compared with normal gait. The TIW also reduced peak external rotation moments compared with normal gait. Conclusions The TIW gait modification seems to be successful in reducing knee joint loading in all three planes during stair ascent, regardless of knee alignment. The success of TIW in varus knee alignments may have important implications for people with medial knee osteoarthritis, or those susceptible to knee osteoarthritis